Crosstalk and ultrasensitivity in protein degradation pathways
Protein turnover is vital to cellular homeostasis. Many proteins are degraded efficiently only after they have been post-translationally “tagged” with a polyubiquitin chain. Ubiquitylation is a form of Post-Translational Modification (PTM): addition of a ubiquitin to the chain is catalyzed by E3 lig...
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| Published in | PLoS computational biology Vol. 16; no. 12; p. e1008492 |
|---|---|
| Main Authors | , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
Public Library of Science
28.12.2020
Public Library of Science (PLoS) |
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| Abstract | Protein turnover is vital to cellular homeostasis. Many proteins are degraded efficiently only after they have been post-translationally “tagged” with a polyubiquitin chain. Ubiquitylation is a form of Post-Translational Modification (PTM): addition of a ubiquitin to the chain is catalyzed by E3 ligases, and removal of ubiquitin is catalyzed by a De-UBiquitylating enzyme (DUB). Nearly four decades ago, Goldbeter and Koshland discovered that reversible PTM cycles function like on-off switches when the substrates are at saturating concentrations. Although this finding has had profound implications for the understanding of switch-like behavior in biochemical networks, the general behavior of PTM cycles subject to synthesis and degradation has not been studied. Using a mathematical modeling approach, we found that simply introducing protein turnover to a standard modification cycle has profound effects, including significantly reducing the switch-like nature of the response. Our findings suggest that many classic results on PTM cycles may not hold
in vivo
where protein turnover is ubiquitous. We also found that proteins sharing an E3 ligase can have closely related changes in their expression levels. These results imply that it may be difficult to interpret experimental results obtained from either overexpressing or knocking down protein levels, since changes in protein expression can be coupled via E3 ligase crosstalk. Understanding crosstalk and competition for E3 ligases will be key in ultimately developing a global picture of protein homeostasis. |
|---|---|
| AbstractList | [...]the sensitivity of protein concentration to changes in E3 activity for any given protein is largely dependent upon the total expression level of the other proteins.
(B) The case of the traditional GK loop, with no synthesis and degradation; (C) The “Intermediate” model, which introduces synthesis (at a rate Q > 0) and degradation (at a rate δ1 > 0); (D) The “Full” model, which includes synthesis (Q > 0) and to different degradation rates: δ1 for the unmodified substrate and δ2 for the modified substrate.
Since the modification in this model is meant to represent a tag that drives degradation, the rate of degradation for the modified substrate is higher than that of the unmofied substrate (i.e. δ2 > δ1 > 0).
Modified substrate is indicated by the dark, filled circle. https://doi.org/10.1371/journal.pcbi.1008492.g001 Adding synthesis and degradation to a PTM cycle Even though E3 ligases generally attach long ubiquitin chains to their substrates [4], in order to simplify the problem to an analytically tractable form, we first considered a case with just a single modification state.
Because ubiquitylation actively effects protein degradation, any investigation of the interplay between substrates competing for a protein and post-translational modifications (PTMs) leading to degradation must account for protein turnover.
Unmodified substrate is also synthesized at a constant rate Q. There is a modification enzyme M that catalyzes the addition of the PTM in question, and a demodification enzyme D that catalyzes removal of the modification.
Since these are enzymes, they form enzyme-substrate complexes: D forms a complex with S* and M with S. To simplify the model, neither M nor D are subject to synthesis and degradation. Protein turnover is vital to cellular homeostasis. Many proteins are degraded efficiently only after they have been post-translationally "tagged" with a polyubiquitin chain. Ubiquitylation is a form of Post-Translational Modification (PTM): addition of a ubiquitin to the chain is catalyzed by E3 ligases, and removal of ubiquitin is catalyzed by a De-UBiquitylating enzyme (DUB). Nearly four decades ago, Goldbeter and Koshland discovered that reversible PTM cycles function like on-off switches when the substrates are at saturating concentrations. Although this finding has had profound implications for the understanding of switch-like behavior in biochemical networks, the general behavior of PTM cycles subject to synthesis and degradation has not been studied. Using a mathematical modeling approach, we found that simply introducing protein turnover to a standard modification cycle has profound effects, including significantly reducing the switch-like nature of the response. Our findings suggest that many classic results on PTM cycles may not hold in vivo where protein turnover is ubiquitous. We also found that proteins sharing an E3 ligase can have closely related changes in their expression levels. These results imply that it may be difficult to interpret experimental results obtained from either overexpressing or knocking down protein levels, since changes in protein expression can be coupled via E3 ligase crosstalk. Understanding crosstalk and competition for E3 ligases will be key in ultimately developing a global picture of protein homeostasis. [...]the sensitivity of protein concentration to changes in E3 activity for any given protein is largely dependent upon the total expression level of the other proteins. (B) The case of the traditional GK loop, with no synthesis and degradation; (C) The “Intermediate” model, which introduces synthesis (at a rate Q > 0) and degradation (at a rate δ1 > 0); (D) The “Full” model, which includes synthesis (Q > 0) and to different degradation rates: δ1 for the unmodified substrate and δ2 for the modified substrate. Since the modification in this model is meant to represent a tag that drives degradation, the rate of degradation for the modified substrate is higher than that of the unmofied substrate (i.e. δ2 > δ1 > 0). Modified substrate is indicated by the dark, filled circle. https://doi.org/10.1371/journal.pcbi.1008492.g001 Adding synthesis and degradation to a PTM cycle Even though E3 ligases generally attach long ubiquitin chains to their substrates [4], in order to simplify the problem to an analytically tractable form, we first considered a case with just a single modification state. Because ubiquitylation actively effects protein degradation, any investigation of the interplay between substrates competing for a protein and post-translational modifications (PTMs) leading to degradation must account for protein turnover. Unmodified substrate is also synthesized at a constant rate Q. There is a modification enzyme M that catalyzes the addition of the PTM in question, and a demodification enzyme D that catalyzes removal of the modification. Since these are enzymes, they form enzyme-substrate complexes: D forms a complex with S* and M with S. To simplify the model, neither M nor D are subject to synthesis and degradation. Protein turnover is vital to cellular homeostasis. Many proteins are degraded efficiently only after they have been post-translationally "tagged" with a polyubiquitin chain. Ubiquitylation is a form of Post-Translational Modification (PTM): addition of a ubiquitin to the chain is catalyzed by E3 ligases, and removal of ubiquitin is catalyzed by a De-UBiquitylating enzyme (DUB). Nearly four decades ago, Goldbeter and Koshland discovered that reversible PTM cycles function like on-off switches when the substrates are at saturating concentrations. Although this finding has had profound implications for the understanding of switch-like behavior in biochemical networks, the general behavior of PTM cycles subject to synthesis and degradation has not been studied. Using a mathematical modeling approach, we found that simply introducing protein turnover to a standard modification cycle has profound effects, including significantly reducing the switch-like nature of the response. Our findings suggest that many classic results on PTM cycles may not hold in vivo where protein turnover is ubiquitous. We also found that proteins sharing an E3 ligase can have closely related changes in their expression levels. These results imply that it may be difficult to interpret experimental results obtained from either overexpressing or knocking down protein levels, since changes in protein expression can be coupled via E3 ligase crosstalk. Understanding crosstalk and competition for E3 ligases will be key in ultimately developing a global picture of protein homeostasis.Protein turnover is vital to cellular homeostasis. Many proteins are degraded efficiently only after they have been post-translationally "tagged" with a polyubiquitin chain. Ubiquitylation is a form of Post-Translational Modification (PTM): addition of a ubiquitin to the chain is catalyzed by E3 ligases, and removal of ubiquitin is catalyzed by a De-UBiquitylating enzyme (DUB). Nearly four decades ago, Goldbeter and Koshland discovered that reversible PTM cycles function like on-off switches when the substrates are at saturating concentrations. Although this finding has had profound implications for the understanding of switch-like behavior in biochemical networks, the general behavior of PTM cycles subject to synthesis and degradation has not been studied. Using a mathematical modeling approach, we found that simply introducing protein turnover to a standard modification cycle has profound effects, including significantly reducing the switch-like nature of the response. Our findings suggest that many classic results on PTM cycles may not hold in vivo where protein turnover is ubiquitous. We also found that proteins sharing an E3 ligase can have closely related changes in their expression levels. These results imply that it may be difficult to interpret experimental results obtained from either overexpressing or knocking down protein levels, since changes in protein expression can be coupled via E3 ligase crosstalk. Understanding crosstalk and competition for E3 ligases will be key in ultimately developing a global picture of protein homeostasis. Protein turnover is vital to cellular homeostasis. Many proteins are degraded efficiently only after they have been post-translationally “tagged” with a polyubiquitin chain. Ubiquitylation is a form of Post-Translational Modification (PTM): addition of a ubiquitin to the chain is catalyzed by E3 ligases, and removal of ubiquitin is catalyzed by a De-UBiquitylating enzyme (DUB). Nearly four decades ago, Goldbeter and Koshland discovered that reversible PTM cycles function like on-off switches when the substrates are at saturating concentrations. Although this finding has had profound implications for the understanding of switch-like behavior in biochemical networks, the general behavior of PTM cycles subject to synthesis and degradation has not been studied. Using a mathematical modeling approach, we found that simply introducing protein turnover to a standard modification cycle has profound effects, including significantly reducing the switch-like nature of the response. Our findings suggest that many classic results on PTM cycles may not hold in vivo where protein turnover is ubiquitous. We also found that proteins sharing an E3 ligase can have closely related changes in their expression levels. These results imply that it may be difficult to interpret experimental results obtained from either overexpressing or knocking down protein levels, since changes in protein expression can be coupled via E3 ligase crosstalk. Understanding crosstalk and competition for E3 ligases will be key in ultimately developing a global picture of protein homeostasis. Protein turnover is vital to cellular homeostasis. Many proteins are degraded efficiently only after they have been post-translationally “tagged” with a polyubiquitin chain. Ubiquitylation is a form of Post-Translational Modification (PTM): addition of a ubiquitin to the chain is catalyzed by E3 ligases, and removal of ubiquitin is catalyzed by a De-UBiquitylating enzyme (DUB). Nearly four decades ago, Goldbeter and Koshland discovered that reversible PTM cycles function like on-off switches when the substrates are at saturating concentrations. Although this finding has had profound implications for the understanding of switch-like behavior in biochemical networks, the general behavior of PTM cycles subject to synthesis and degradation has not been studied. Using a mathematical modeling approach, we found that simply introducing protein turnover to a standard modification cycle has profound effects, including significantly reducing the switch-like nature of the response. Our findings suggest that many classic results on PTM cycles may not hold in vivo where protein turnover is ubiquitous. We also found that proteins sharing an E3 ligase can have closely related changes in their expression levels. These results imply that it may be difficult to interpret experimental results obtained from either overexpressing or knocking down protein levels, since changes in protein expression can be coupled via E3 ligase crosstalk. Understanding crosstalk and competition for E3 ligases will be key in ultimately developing a global picture of protein homeostasis. Previous work has shown that substrates of Post-Translational Modification (PTM) cycles can have coupled responses if those substrates share enzymes. This implies that modifications leading to substrate degradation (e.g. ubiquitylation by an E3 ligase) could introduce coupling in concentrations of substrates sharing a ligase. Using mathematical models, we found adding protein turnover to a PTM cycle diminishes both sensitivity and ultrasensitivity, particularly in models admitting long ubiquitin chains. We also found that proteins sharing an E3 ligase can indeed have coupled changes in both expression and sensitivity to signals. These results imply that accounting for crosstalk in protein degradation networks is crucial for the interpretation of results from a wide variety of common experimental perturbations to living systems. |
| Audience | Academic |
| Author | Mallela, Abhishek Nariya, Maulik K. Deeds, Eric J. |
| AuthorAffiliation | 4 Institute for Quantitative and Computational Biosciences, University of California, Los Angeles, Los Angeles, California, United States of America 2 Laboratory of Systems Pharmacology, Harvard Medical School, Boston, Massachusetts, United States of America 1 Department of Mathematics, University of California Davis, Davis, California, United States of America 3 Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, California, United States of America King’s College London, UNITED KINGDOM |
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| SubjectTerms | Analysis Biodegradation Biology and Life Sciences Catalysis Cell cycle Crosstalk Degradation Enzymes Gene expression Homeostasis Humans Kinases Observations Physiological aspects Post-translation Protein Processing, Post-Translational Protein turnover Proteins Proteins - chemistry Proteolysis Research and Analysis Methods Sensitivity analysis Substrates Synthesis Ubiquitin Ubiquitin-proteasome system Ubiquitin-protein ligase Ubiquitin-Protein Ligases - metabolism |
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| Title | Crosstalk and ultrasensitivity in protein degradation pathways |
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